The Cardiometabolic-to-Cancer Axis

Q: What is the clinical evidence from this study?

Study design: Editorial. Population: Cardiovascular-kidney-metabolic (CKM) syndrome (n=448323). Intervention: Advancing cardiovascular-kidney-metabolic (CKM) stage vs. Lower CKM stage. Primary outcome: Incident cancer.

Q: What does this research mean for the field?

Advancing cardiovascular-kidney-metabolic stage is associated with a graded increase in overall cancer incidence, with the greatest risk increment occurring at the transition from stage 2 to stage 3. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Adithya Yadalam; Yan V. Sun

doi:10.1016/j.jaccao.2026.06.004

August 1, 2026JACC CardioOncologyOpen Access

The Cardiometabolic-to-Cancer Axis

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Graphical abstract published by JACC CardioOncology — Graphical abstract · Published by JACC CardioOncology · CC BY-NC-ND

Why the study?

Does advancing cardiovascular-kidney-metabolic (CKM) stage increase the risk of incident cancer in a population-based cohort?

Key Points

Determine whether the cardiovascular-kidney-metabolic staging continuum captures incident cancer risk beyond its constituent risk factors and evaluate underlying proteomic and metabolomic mediators.
Evaluated 448,323 UK Biobank participants followed for a median of 4.3 years using an adjacent-stage design and Fine–Gray competing-risk regression modeling.
Profiled 2,921 Olink plasma proteins and 220 nuclear magnetic resonance metabolic markers to conduct mediation analyses and Gene Ontology pathway enrichment across CKM stages 0 to 4.
Advancing CKM stage was associated with a graded increase in overall cancer incidence, localizing the greatest oncologic risk increment to the transition from stage 2 to stage 3.
Mediation analyses identified a conserved core of 15 recurring mediators (including TNFRSF proteins, GDF15, CXCL13, PLAUR, IL2RA, and CD27) along with an evolving lipoprotein-particle shift.
Incremental cancer-risk discrimination provided by CKM staging over its individual constituent components was statistically significant but clinically negligible (ΔC-index 0.0014).

Structured PICO

Does advancing cardiovascular-kidney-metabolic (CKM) stage increase the risk of incident cancer in a population-based cohort?

P

Population

448,323 UK Biobank participants followed for a median of 4.3 years to evaluate the association between cardiovascular-kidney-metabolic stage and incident cancer.

E

Exposure

Advancing cardiovascular-kidney-metabolic (CKM) stage (stages 0-4)

C

Comparator

Lower CKM stages (adjacent-stage design)

O

Outcome

Incident cancer (overall and site-specific)hard clinical

Limitations

Clinically negligible incremental improvement in cancer-risk discrimination (ΔC-index 0.0014)
Mediation estimates frequently fell outside the [0,1] interval
Potential reverse causation at advanced stages
UK Biobank's healthy-volunteer selection and limited ancestral diversity
Residual confounding by age, smoking, and other constituents
Incremental improvement in cancer-risk discrimination was clinically negligible (ΔC-index 0.0014)
Possible reverse causation at advanced stages due to attrition of proteomic mediators under 5-year latency exclusion
Residual confounding by age, smoking, and other CKM constituents cannot be fully excluded

Implication

The cardiovascular-kidney-metabolic (CKM) continuum reflects shared oncologic and cardiometabolic biology, characterized by a stage-ordered evolution of immune dysregulation and lipoprotein remodeling, highlighting potential shared therapeutic targets.

Abstract

C ardiovascular disease (CVD) and cancer together account for the majority of mortality in developed nations.

Discussion

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Cite This Study

Yadalam et al. (2026) conducted an editorial in Cardiovascular-kidney-metabolic (CKM) syndrome (n=448,323). Advancing cardiovascular-kidney-metabolic (CKM) stage vs. Lower CKM stage was evaluated on Incident cancer.

synapsesocial.com/papers/6a8c3805cc5fa73295d48baf https://doi.org/10.1016/j.jaccao.2026.06.004

View Full Paper

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The Cardiometabolic-to-Cancer Axis

Key Points

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

The Cardiometabolic-to-Cancer Axis

Key Points

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

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